REVIEW article
Front. Immunol.
Sec. NK and Innate Lymphoid Cell Biology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1557644
This article is part of the Research TopicNovel Chimeric Antigen Receptor (CAR) Designs in engineering NK cells for CancerView all 4 articles
Designs of NKG2D-Based Immunotherapeutics for Cancer
Provisionally accepted
- 1The Ohio State University, Columbus, United States
- 2College of Medicine, The Ohio State University, Columbus, Ohio, United States
- 3Institute of Medical Engineering & Translational Medicine, Medical College, Tianjin University, Tianjin, China, Tianjin, China
- 4The University of Hong Kong, Pokfulam, Hong Kong, SAR China
- 5Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong, SAR China
- 6Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States
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Natural killer group 2 D (NKG2D) receptor, one of the activation receptors on NK cells, has gained increasing attention in recent years because its ligands are widely expressed in most cancers.Naturally, NKG2D reacts to 8 different stress-induced ligands, MICA/B, and ULBP1-6. Despite being genomically conserved between human and mouse, NKG2D transcripts have splice variants that can differentiate the two. hNKG2D or mNKG2D (both long and short transcripts) interacts with DAP10 only in human but DAP10/12 in mouse, switching on different effector functions such as IFN-γ production and cytotoxicity. Full-length, extracellular or cytoplasmic domains have been used to construct chimeric antigen receptors (CAR) or implement into the antibody structures including bispecific antibodies. Interestingly, most of the NKG2D CARs, either on T cells or NK cells are investigated in preclinical models of solid tumors. In this article, we reviewed the majority of published NKG2D-based CAR and antibody designs, comparing their respective advantages and disadvantages. We also elaborated how these CARs and antibodies were tested in preclinical cancer models and clinical trials in this review article.
Keywords: NKG2D, Immunotherapy, CAR-T therapy, NK cell therapy, Cancer
Received: 08 Jan 2025; Accepted: 03 Jun 2025.
Copyright: © 2025 Han, Wang, Chan and Chan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Godfrey Chi-Fung Chan, The University of Hong Kong, Pokfulam, 999077, Hong Kong, SAR China
Wing Keung Chan, Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, 43210, Ohio, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.